Observations made initially by our group suggest that the study of the relative accumulation of the lithium ion (Li ion) by erythrocytes might help to identify a distinct subgroup of depressed patients and perhaps even a biological abnormality in these patients. We plan to continue these studies and to extend them in several ways. Our clinical biochemical test will be the measurement of erythrocyte Li ion-sodium (Na ion) ion counterflow actively directly, by the use of an in vitro incubation procedure developed by us. This will be measured in a group of patients with affective disorders as well as in normal control subjects. In addition, a variety of clinical parameters will be assessed, with particular attention focused on the SCL-90 symptom profile. This is because of our preliminary observation that elevated scores in bipolar patients on three scales of the SCL-90 seem related to a poor antidepressant response to lithium and to lower erythrocyte Li ion accumulation than in typical bipolar patients. We intend to examine the relationship of this clinical feature to Li ion-Na ion counterflow activity and to the antidepressant effect of Li ion. Our aim is to identify by the use of such parameters, more homogeneous subgroups of patients with affective illness. Furthermore, as there is evidence that Li ion treatment inhibits counterflow activity, and that the extent of this inhibition varies among subjects, we intend to examine whether this pharmacological action of Li ion is related to its antidepressant effect.